TY - JOUR
T1 - A randomized controlled, phase 2 trial of the viral serpin serp-1 in patients with acute coronary syndromes undergoing percutaneous coronary intervention
AU - Tardif, Jean Claude
AU - L'Allier, Philippe L.
AU - Grégoire, Jean
AU - Ibrahim, Reda
AU - McFadden, Grant
AU - Kostuk, William
AU - Knudtson, Merril
AU - Labinaz, Marino
AU - Labinaz, Ron Waksman
AU - Pepine, Carl J.
AU - Macaulay, Colin
AU - Guertin, Marie Claude
AU - Lucas, Alexandra
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/12
Y1 - 2010/12
N2 - Background-Vascular inflammation can lead to plaque instability and acute coronary syndromes (ACS). Viruses produce potent immunomodulating proteins that regulate key inflammatory pathways. A myxoma virus- derived serpin Serp-1 reduces inflammatory cell invasion and plaque growth in vascular injury models. Our objective was to evaluate the safety and efficacy of Serp-1 in patients with ACS undergoing percutaneous coronary intervention. Methods and Results-This double-blind pilot trial included 48 ACS patients undergoing percutaneous coronary intervention randomly assigned to Serp-1 at doses of 5 μg/kg (n=19) or 15 μg/kg (n=17) or to placebo (n=12). Serp-1 was given by intravenous bolus immediately before intervention and 24 and 48 hours later. Patients were assessed for safety (primary objective) and efficacy outcomes, including biomarker analysis. In-stent neointimal hyperplasia was evaluated by intravascular ultrasound at 6 months. Key safety outcomes including coagulation parameters and adverse events did not differ between Serp-1 and placebo groups. A dose-dependent reduction in troponin I levels was observed with Serp-1 at 8, 16, 24, and 54 hours (P<0.05) and in creatine kinase-MB levels at 8, 16, and 24 hours after dose (P<0.05). The composite of death, myocardial infarction, or coronary revascularization occurred in 2 of 12 patients with placebo, 5 of 19 in the low-dose group, and none of 17 patients with the high-dose (P=0.058). Intravascular ultrasound did not detect changes in neointimal hyperplasia among groups. Conclusions-This is the first study of a viral serpin demonstrating its safety in ACS patients. The significant reduction in myocardial damage biomarkers supports further assessment of Serp-1 in ACS patients undergoing stent deployment.
AB - Background-Vascular inflammation can lead to plaque instability and acute coronary syndromes (ACS). Viruses produce potent immunomodulating proteins that regulate key inflammatory pathways. A myxoma virus- derived serpin Serp-1 reduces inflammatory cell invasion and plaque growth in vascular injury models. Our objective was to evaluate the safety and efficacy of Serp-1 in patients with ACS undergoing percutaneous coronary intervention. Methods and Results-This double-blind pilot trial included 48 ACS patients undergoing percutaneous coronary intervention randomly assigned to Serp-1 at doses of 5 μg/kg (n=19) or 15 μg/kg (n=17) or to placebo (n=12). Serp-1 was given by intravenous bolus immediately before intervention and 24 and 48 hours later. Patients were assessed for safety (primary objective) and efficacy outcomes, including biomarker analysis. In-stent neointimal hyperplasia was evaluated by intravascular ultrasound at 6 months. Key safety outcomes including coagulation parameters and adverse events did not differ between Serp-1 and placebo groups. A dose-dependent reduction in troponin I levels was observed with Serp-1 at 8, 16, 24, and 54 hours (P<0.05) and in creatine kinase-MB levels at 8, 16, and 24 hours after dose (P<0.05). The composite of death, myocardial infarction, or coronary revascularization occurred in 2 of 12 patients with placebo, 5 of 19 in the low-dose group, and none of 17 patients with the high-dose (P=0.058). Intravascular ultrasound did not detect changes in neointimal hyperplasia among groups. Conclusions-This is the first study of a viral serpin demonstrating its safety in ACS patients. The significant reduction in myocardial damage biomarkers supports further assessment of Serp-1 in ACS patients undergoing stent deployment.
KW - Acute coronary syndrome
KW - Coronary angioplasty
KW - Inflammation
KW - Serpin
KW - Stent
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U2 - 10.1161/CIRCINTERVENTIONS.110.953885
DO - 10.1161/CIRCINTERVENTIONS.110.953885
M3 - Article
C2 - 21062996
AN - SCOPUS:79953287029
SN - 1941-7640
VL - 3
SP - 543
EP - 548
JO - Circulation: Cardiovascular Interventions
JF - Circulation: Cardiovascular Interventions
IS - 6
ER -